Container closure delivery system

ABSTRACT

A container closure delivery system that is suitable for lyophilized pharmaceutical injectable powder products is disclosed. The system comprises storage stable powder formulations and a container closure assembly design wherein the formulation can be filled and lyophilized with a standard fill finish equipment, and the formulations and lyophilization processes are optimized to produce a powder that readily dissolves upon contact with a diluent, thereby facilitating the direct injection of the lyophilized product without the need for a separate reconstitution/mixing/priming step.

RELATED PATENT APPLICATIONS

This application is a continuation-in-part application of U.S. patentapplication Ser. No. 11/172,064, filed on Jun. 30, 2005, which claimsthe benefit of U.S. Provisional Application No. 60/640,625, filed onDec. 30, 2004, each incorporated in its entirety by reference herein.

TECHNICAL FIELD

The field of the present invention is a container closure deliverysystem that is suitable for lyophilized pharmaceutical injectableproducts and which facilitates the easy, direct injection of thelyophilized product without the need for a reconstitution/mixing step ofthe powder and a liquid diluent.

BACKGROUND OF THE INVENTION

Due to continued advances in genetic and cell engineering technologies,proteins known to exhibit various pharmacological actions in vivo arecapable of production in large amounts for pharmaceutical applications.However, one of the most challenging tasks in the development of proteinpharmaceuticals is to deal with the inherent physical and chemicalinstabilities of such proteins, especially in aqueous dosage forms. Totry to understand and maximize the stability of protein pharmaceuticalsand any other usable proteins, many studies have been conducted,especially in the past two decades. These studies have covered manyareas, including protein folding and unfolding/denaturation, mechanismsof chemical and physical instabilities of proteins, as well as variousmeans of stabilizing proteins in aqueous form; see, e.g., Manning etal., Pharm Res., 1989; 6:903-918; Arakawa et al., Adv Drug Deliv Rev.,2001; 46:307-326; Wang W., Int J Pharm., 1999; 185:129-188; Chen T.,Drug Dev Ind Pharm., 1992; 18:1311-1354, and references cited therein.

Because of the instability issues associated with the aqueous dosageforms, powder formulations are generally preferred to achieve sufficientstability for the desired shelf life of the product. Various techniquesto prepare dry powders have been known, substantiated and practiced inthe pharmaceutical and biotech industry. Such techniques includelyophilization, spray-drying, spray-freeze drying, bulk crystallization,vacuum drying, and foam drying. Lyophilization (freeze-drying) is oftena preferred method used to prepare dry powders (lyophilizates)containing proteins. Various methods of lyophilization are well known tothose skilled in the art; see, e.g., Pikal M J., In: Cleland J L, LangerR. eds. Formulation and Delivery of Proteins and Peptides. Washington,D.C.: American Chemical Society; 1994:120-133; Wang W., Int J Pharm.2000; 203:1-60, and references cited therein.

The lyophilization process consists if three stages: freezing, primarydrying, and secondary drying. Because the protein product is maintainedfrozen throughout drying process, lyophilization provides the followingadvantages over alternative techniques: minimum damage and loss ofactivity in delicate, heat-liable materials; speed and completeness ofrehydration; the possibility of accurate, clean dosing into finalproduct containers so that particulate and bacterial contamination isreduced; permits product reconstitution at a higher concentration thanit was at the time of freezing; and permits storage of the product atambient temperatures. The latter can be particularly useful for hospitalproducts in areas that do not have ready access to freezers, especiallyultra-cold freezers.

Unfortunately, even in solid dosage forms, some proteins can berelatively unstable and this instability may be a product of thelyophilization method used for preparing the solid dosage forms and/orthe inherent instability of the actual solid dosage formulationsthemselves. For example, in certain instances, lyophilization processingevents can force a protein to undergo significant chemical and physicalchanges. Such processing events include concentration of salts,precipitation, crystallization, chemical reactions, shear, pH, amount ofresidual moisture remaining after freeze-drying, and the like. Suchchemical and physical changes include, e.g., formation of dimer or otherhigher order aggregates, and unfolding of tertiary structure.Unfortunately, these changes may result in loss of activity of theprotein, or may result in significant portions of the active materialsin the drug having been chemically transformed into a degradationproduct or products which may actually comprise an antagonist for thedrug or which may give rise to adverse side effects. In addition to theinstabilities incurred upon proteins because of the inherent steps ofthe lyophilization process, other disadvantages of lyophilizationinclude: long and complex processing times; high energy costs; andexpensive set up and maintenance of the lyophilization facilities. Assuch, use of lyophilization is usually restricted to delicate,heat-sensitive materials of high value. Additionally, lyophilizedpowders are typically formed as cakes, which require additional grindingand milling and optionally sieving processing steps to provide flowingpowders. To try to understand and to optimize protein stability duringlyophilization and after lyophilization, many studies have beenconducted; see, e.g., Gomez G. et al., Pharm Res. 2001; 18:90-97;Strambini G B., Gabellieri E., Biophys J., 1996; 70:971-976; Chang B S.et al., J Pharm Sci., 1996; 85:1325-1330, Pikal M J., Biopharm, 1990;3:9, Izutsu K. et al., Pharm. Res., 1994; 11-995, Overcashier D E., JPharm Sci., 1999; 88:688, Schmidt E A. et al., J Pharm Sci., 1999;88:291, and references cited therein.

In order to allow for parenteral administration of these powdered drugs,the drugs must first be placed in liquid form. To this end, the drugsare mixed or reconstituted with a diluent before being deliveredparenterally to a patient. The reconstitution procedure must beperformed under sterile conditions, and in some procedures forreconstituting, maintaining sterile conditions is difficult. One way ofreconstituting a powdered drug is to inject a liquid diluent directlyinto a drug vial containing the powdered drug. This can be performed byuse of a combination-syringe and syringe needle having diluent containedtherein and drug vials which include a pierceable rubber stopper. Themethod of administration goes as follows: 1) the rubber stopper of thedrug vial is pierced by the needle and the liquid in the syringeinjected into the vial; 2) the vial is shaken to mix the powdered drugwith the liquid; 3) after the liquid and drug are thoroughly mixed, ameasured amount of the reconstituted drug is then drawn into thesyringe; 4) the syringe is then withdrawn from the vial and the drugthen be injected into the patient.

For people requiring frequent parenteral administration of drugs, it iscommon practice for those people to be provided with home-use kits whichmay include injection cartridges, pre-filled syringes, pen injectorsand/or autoinjectors to be used for the purpose of self-administration.Autoinjectors incorporating needled injection mechanisms are well knownand thought to exhibit several advantages relative to simple hypodermicsyringes. Such needled autoinjectors generally include a body orhousing, a needled syringe or similar device, and one or more drivemechanisms for inserting a needle into the tissue of the subject anddelivering a desired dose of liquid medicament through the insertedneedle. To date, all known autoinjector devices have been used withliquid formulations. There still exists a need for an autoinjector thatcan used to deliver powdered formulations.

Other methods of administration of powdered drugs include the use ofdual-chambered injection cartridges and/or pre-filled syringe systems.Injection cartridges of the dual-chamber type are well-known and havefound a wide use. They are used together with various types of injectionapparatuses which serve to hold the cartridge as it is readied forinjection and as injections are subsequently administered. Injectioncartridges of the dual-chamber type generally comprise a cylindricalbarrel, which is shaped like a bottleneck at its front end and has anopen rear end. The front end is closed by a septum of rubber or othersuitable material, which is secured in place by means of a capsule. Thiscapsule has a central opening where the septum is exposed and may bepierced by a hollow needle to establish a connection with the interiorof the cartridge; see e.g., U.S. Pat. No. 5,435,076 and references citedtherein.

Dual-chambered pre-filled syringe systems are well known and have foundwide commercial use; see e.g., U.S. Pat. Nos. 5,080,649; 5,833,653;6,419,656; 5,817,056; 5,489,266, and references cited therein.Pre-filled syringes of the dual-chambered type generally comprise anactive ingredient which is lyophilized in one chamber, while a secondchamber of the syringe contains a solvent that is mixed with the activesubstance immediately before application. In such devices, in order tofacilitate the movement of the syringe plunger against compression ofair, the chamber containing the lyophilized product typically has largehead space and some additional mechanism, e.g., rotation of the plunger,screwing in the plunger, is necessary. As a result, the reconstituteddrug needs to primed to remove large volumes of air prior to injection;see e.g., U.S. Pat. No. 6,817,987 which describes a hypodermic syringewhich holds a solvent and a soluble component (medicament) and whereinthe solvent and medicament are mixed as the user presses and thenreleases the plunger of the syringe. Upon complete mixing, the userattaches a needle and then rotates the plunger of the syringe to allowfor the injection.

Several syringe devices of various configurations and various processesof lyophilization have been described in, e.g., U.S. Pat. Nos.5,752,940; 5,876,372; 6,149,628; 6,440,101, and references citedtherein. Importantly, in each instance, the devices comprise multipleparts and require at least a two step, two directional reconstitutionprocess for the delivery of the lyophilized powdered drug. Other devicesused for reconstitution and delivery of powdered drugs are described in,e.g., U.S. Pat. Nos. 4,328,802; 4,410,321; 4,411,662; 4,432,755;4,458,733; 4,898,209; 4,872,867; 3,826,260, and references citedtherein.

Unfortunately, because all of these known methods require thoroughreconstitution/mixing of the lyophilized product into the diluent priorto injection, they can typically involve lengthy procedures (in excessof 10 steps) in order to reconstitute the solid drug into a liquidformulation prior to administration. Such lengthy reconstitution stepscan be complex, arduous and tedious for the patient and may renderinjection of the lyophilized product unfeasible. Moreover, thesecomplicated procedures present risks of foaming, risk of contamination,and risk of accidental needle pricks. There clearly still exists a needfor improved delivery devices and methods.

Co-pending U.S. patent application Ser. No. 11/172,064 ('064) providesan advancement in the technology and relates to a container closureassembly suitable for lyophilized pharmaceutical injectable products anddesigned to provide for direct injection of a lyophilized productwithout the need for a reconstitution/mixing/priming step of the powderand diluent prior to injection. The components of the disclosedcontainer closure assembly were designed to function in a manufacturingfunction and an end user function and, upon completion of thelyophilization process, the assembly has minimal head space to avoid theneed for priming. The disclosed container closure assembly is designedto utilize or be easily adaptable to industry standard or existingfilling systems, thus providing a more economical alternative to priorart devices.

The present invention provides an improved alternative container closuredesign which facilitates the easy, direct injection of the lyophilizedproduct without the need for a reconstitution/mixing/priming step of thepowder and a liquid diluent by the end user. As with the assembliesdescribed in the '064 application, the disclosed container closureassembly is designed to utilize or be easily adaptable to industrystandard or existing filling systems, thus providing a more economicalalternative to prior art devices.

SUMMARY OF THE INVENTION

The container closure assembly of the present invention consists ofthree operating components designed to function in a manufacturingfunction and an end user function: a plug component; a top cupcomponent; and a product container component. The plug component and topcup component are specifically designed to snugly engage with each otherto form a plunger assembly that can then be inserted into the productcontainer. Alternatively, the plunger assembly may be a one piececomponent comprising specific features the top cup component and plugcomponent. The plunger assembly may thus vary in size and configurationand have varying manufacturing and/or end user functionality. Theproduct container component is specifically designed to hold a liquid tobe lyophilized and capable of holding a plunger assembly. The productcontainer may vary in size and configuration but is typicallycylindrical in shape, and has at one end an opening and at the opposingend an ejection port. An important, unique design feature of the productcontainer is a spiral mixing channel that is integrated into the productcontainer at the lower base and which serves to improve product yield.

Importantly, the container closure assembly of the present invention isdesigned to utilize or be easily adaptable to industry standard orexisting lyophilization systems, thus providing an economicalalternative. Upon completion of the lyophilization process, the plungerassembly is compressed such that it compresses the powderedpharmaceutical product, i.e., there is minimum head space between theproduct container and the plunger assembly, and the plunger assemblyserves as a path to allow for the flow of liquid into the containerclosure assembly, i.e., allow for liquid to encounter the powder andrapidly reconstitute without the need for priming. Because of the uniqueassembly design, the container closure assembly facilitates the easy,direct injection of the lyophilized product without the need for areconstitution/mixing/priming step of the powder and a liquid diluent bythe end user.

Another object of the present invention is an improved process for thepreparation of a container closure assembly containing a lyophilizedpowder product. This improved process comprises the following steps: 1)utilizing an industry standard vial manufacturing filling line, theproduct container is loaded into the equipment in a similar manner asregular vials; 2) the product container is filled with liquid activeingredient; 3) a plunger assembly is dropped into an “open” position ontop of the product container, engaged with the product container in thesame manner as lyophilization stoppers are mounted to regular vials; 4)the complete container closure assembly is then placed into thelyophilizer; 5) upon lyophilization, vapor is allowed to escape via theopenings between the plunger assembly and product container; 6) uponcompletion of lyophilization, vertical compression of the lyophilizershelves will seal the plunger assembly into the product container withminimal head space; and 7) the sealed container closure assembly isbonded to provide a tamper resistant assembly which retains thesterility of the active ingredient.

Another object of the present invention is an improved method for theadministration of a lyophilized pharmaceutical powder product using thecontainer closure system of the present invention. In one embodiment,this improved method of administration comprises the following steps: 1)a tangential force is applied to the tab seal at the top end of thesealed container closure assembly containing the lyophilized powderproduct to allow attachment via friction fit to either a luer-lock orluer-slip syringe containing the diluent; 2) the detachable base at theejection port end of the container closure assembly is detached, thusexposing a tip for the attachment of a standard type needle; 3) astandard type needle is attached to said exposed tip of the containerclosure assembly; 4) the injection is then initiated as normal byinserting the needle into the injection site; and 5) force is applied tothe syringe plunger whereupon the diluent in the syringe will be forcedthrough the container closure assembly, encounter the lyophilized powderand rapidly reconstitute the powder to allow the liquefied productmixture to flow into the injection site, completing the injection.Importantly, there is no requirement for a reconstitution/mixing/primingstep of the powder and diluent by the end user.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows an elevation perspective view from the upper base of aproduct container contemplated for use in the container closure assemblyof the present invention.

FIG. 2 shows a perspective view of a product container contemplated foruse in the container closure assembly of the present invention, shownalong a vertical plane.

FIG. 3 shows an elevation perspective view from the bottom of a top cupcomponent contemplated for use in the container closure assembly of thepresent invention.

FIG. 4 shows a perspective view of a top cup component contemplated foruse in the container closure assembly of the present invention.

FIG. 5 shows a perspective view of a plug portion contemplated for usein the container closure assembly of the present invention.

FIG. 6 is a perspective view showing the arrangement of elements andparts for one embodiment of the container closure assembly of thepresent invention.

FIG. 7 shows a perspective view of an embodiment of the containerclosure assembly whereupon a plunger assembly consisting of a top cupcomponent and a plug component are installed upon the product containerafter the filling the product container with liquid active ingredientand prior to placement of the container closure assembly within a freezedrying apparatus, i.e., the plunger assembly is installed in an “open”position in the product container.

FIG. 8 shows a perspective view of an embodiment of the containerclosure assembly upon completion of the freeze drying cycle whereuponthe liquid active ingredient has formed into a dry powder and theplunger assembly has been compressed by the freeze dryer shelves tocreate a sealed container closure assembly.

FIG. 9 shows a perspective view of an alternative product containerdesign contemplated for use in the container closure assembly of thepresent invention, wherein the ejection port of the product containercomprises a nozzle spray tip for nasal delivery.

FIG. 10 is a graph depicting the ‘gradient delivery’ injection profileassociated with the administration of a powdered drug using the powderformulations, lyophilization processes, and container closure assemblyof the present invention. Protein concentration is plotted versuscumulative injection volume.

FIG. 11 is a graph depicting an injection profile representative ofthose associated with the administration of a powdered drug using priorart devices which require a reconstitution and/or mixing step of thepowdered drug with a diluent prior to injection. Protein concentrationis plotted versus cumulative injection volume.

DETAILED DESCRIPTION OF THE INVENTION

As those in the art will appreciate, the foregoing detailed descriptiondescribes certain preferred embodiments of the invention in detail, andis thus only representative and does not depict the actual scope of theinvention. Before describing the present invention in detail, it isunderstood that the invention is not limited to the particular aspectsand embodiments described, as these may vary. It is also to beunderstood that the terminology used herein is for the purpose ofdescribing particular embodiments only, and is not intended to limit thescope of the invention defined by the appended claims.

Referring now in more detail to the drawings, FIGS. 1 and 2 depict theproduct container 100 of the described container closure assembly 600.The product container 100 is constructed of a suitable plastic materialand is cylindrical in shape. The upper base 110 of the product container100 is completely open. The product container 100 has a hollow circularinside to create sufficient holding volume of liquid active ingredientand specifically designed to accept a plunger assembly 500 which isformed when the top cup component 300 is fully engaged with the plugcomponent 400. The lower base 120 comprises a coaxial hollow ejectionport 130 where an internal tube 140 is defined through which the liquidactive ingredient flows toward an injection needle. The outer surfacearea of the ejection port 130 is of a sufficient radius to allow for afriction fit of a standard type luer slip or luer lock syringe needleattachment at the tip of the port. A locking ridge 170 is integratedinto the sidewall of the product container 100 such that upon fullinsertion of the plunger assembly, the plunger assembly cannot beremoved. A spiral mixing channel 190 is integrated into the productcontainer at the lower base 120. The product container 100 depicted inFIG. 2 comprises a staked needle 160 at the ejection port 130.

FIGS. 3 and 4 depict the top cup component 300 of the describedcontainer closure assembly 600. This top cup component 300 is envisagedto be constructed out of a suitable plastic material. The top cupcomponent 300 has a hollow circular inside 310 and is constructed toaccept and fully engage with the plug portion 400 to create a plungerassembly 500 for the container closure assembly 600. In FIG. 4, a tabseal 330 is depicted and at the base of the tab seal 330 is a break orscoring point 340 formed such that when the tab seal 330 is torqued, itwill break off at this point 340. Upon removal of the tab seal 330, afluid transfer channel is defined which facilitates the flow of diluentfrom an attached syringe through the assembled plunger assembly 500 toencounter the lyophilized powder in the product container 100. A luerlock tab 320 is depicted where a standard type luer slip syringe(containing diluent) can be frictionally attached after removal of a tabseal 330 to provide a means to administer reconstituted lyophilizedpowder to a patient when force is applied to the syringe plunger.

FIG. 5 shows the plug component 400 of the described container closureassembly 600. This plug component 400 is envisaged to be constructed ofa suitable plastic material and designed to fully engage with the topcup component 300 with a snug fit to form a plunger assembly 500. Theproximal end 410 of the plug component 400 is designed such that whenfully engaged with the top cup component 300 there is minimal fluid headspace, i.e., minimal holdup volume of the transfer diluent. The distalend 420 of the plug component 400 is designed such that when the plungerassembly is fully engaged with the product container 100 the plungerassembly rests directly on top of the powdered active ingredient andthere is minimal fluid head space. A fluid transfer channel 430extending axially from the proximal end to the distal end on the outsideof the plug component 400 facilitates the flow of diluent through saidplunger assembly 500.

FIG. 6 depicts the arrangement of the top cup component 300, the plugportion 400, and the product container 100 (containing liquid activeingredient 200) for one embodiment of the container closure assembly ofthe present invention prior to being loaded into a industry standardvial/syringe/cartridge manufacturing filling line. In the embodimentdepicted in FIG. 6, the product container comprises a staked needle 160at the ejection port which will be covered by a detachable base 195which serves as a needle shield.

FIG. 7 shows a perspective view of the container closure assembly 600embodiment of FIG. 6 whereupon the plunger assembly 500 (consisting of atop cup component fully engaged with the plug component) is installedupon the product container 100 after the filling the product container100 with liquid active ingredient 200 and prior to placement of thecontainer closure assembly within a freeze drying apparatus, i.e., theplunger assembly 500 is installed in an “open” position in the productcontainer 100 and the product container 100 rests in the needleshield/base 195.

FIG. 8 shows a perspective view of the container closure assembly 600embodiment of FIG. 7 upon completion of the freeze drying cyclewhereupon the liquid active ingredient has formed into a dry powder (notvisible) and the plunger assembly 500 has fully engaged with the productcontainer 100 to compress the powdered active ingredient with minimalfluid head space.

FIG. 9 depicts an alternative product container design contemplated foruse in the container closure assembly of the present invention, whereinthe ejection port of the product container comprises a nozzle spray tip198 for nasal delivery.

Contemplated for use in the container closure assembly of the presentinvention are storage stable powder formulations of pharmaceuticalproducts. Importantly, the powder formulations of the present inventionare optimized to produce powders which provide for “rapid” dissolutionof the lyophilized powder, i.e., the powders are readily and immediatelydissolved upon contact with a liquid diluent. The lyophilized powders ofthe present invention comprise an active ingredient, e.g., protein, anda stabilizer. Stabilizers are added to the lyophilized formulation toenhance the stability of active ingredient. Stabilizers such as, e.g.,surfactants, sugars, polymers, antioxidants, amino acids, salts, can beadded to stabilize active ingredient during freezing process; andadditives that can replace hydrogen bonds of water during dehydrationprocess, e.g., sucrose, trehalose, lactose, or other sugars, can beadded to stabilize pharmaceuticals by maintaining their nativestructure.

In order to maintain large surface area, the powder formulations mayfurther comprise bulking agents that can form crystalline matrices(e.g., mannitol, glycine, polyethylene glycol, and the like).Alternatively, other glassy bulking agents like sugars and polymers,e.g., sucrose, trehalose, lactose, proteins, dextran and itsderivatives, cyclodextran, carboxymethylcellulose, PVA, PVC, starch andits derivatives, can be added to the formulation.

The powder formulations may further comprise surfactants and buffers.Such surfactants include polysorbate 80 (or Tween 80), polysorbate 20(or Tween 20), or pluronics. Such buffers include, e.g., phosphate,histidine, imidazole, citrate, acetate, succinate, glutamate, Tris andglycine can be added to keep desirable pH.

In order to minimize the mass that needs to be dissolved duringinjection, the formulation can be composed mostly by active ingredients.For example, protein or peptide products can be lyophilized with thefinal solid content of 95% of protein or peptide and 5% of stabilizer.

Pharmaceutical products (active ingredients) contemplated for useinclude small molecules, vaccines, live or attenuated cells,oligonucleotides, DNA, peptides, antibodies, and recombinant ornaturally occurring proteins, whether human or animal, useful forprophylactic, therapeutic or diagnostic application. The activeingredient can be natural, synthetic, semi-synthetic or derivativesthereof. In addition, active ingredients of the present invention can beperceptible. A wide range of active ingredients are contemplated. Theseinclude but are not limited to hormones, cytokines, hematopoieticfactors, growth factors, antiobesity factors, trophic factors,anti-inflammatory factors, and enzymes One skilled in the art willreadily be able to adapt a desired active ingredient to the powderedformulations of present invention.

Active ingredients can include but are not limited to insulin, gastrin,prolactin, human growth hormone (HGH), adrenocorticotropic hormone(ACTH), thyroid stimulating hormone (TSH), luteinizing hormone (LH),follicle stimulating hormone (FSH), human parathyroid hormone (PTH),glucagons-like peptide 1 (GLP-1), growth hormone-releasing factor (GRF),human chorionic gonadotropin (HCG), motilin, interferons (alpha, beta,gamma), interleukins (IL-1 to IL-12), interleukin-1 receptor antagonists(IL-Ira), tumor necrosis factor (TNF), tumor necrosis factor-bindingprotein (TNF-bp), erythropoietin (EPO), granulocyte-colony stimulatingfactor (G-CSF), stem cell factor (SCF), leptin (OB protein), brainderived neurotrophic factor (BDNF), glial derived neurotrophic factor(GDNF), neurotrophic factor 3 (NT3), fibroblast growth factors (FGF),neurotrophic growth factor (NGF), bone growth factors such asosteoprotegerin (OPG), insulin-like growth factors (IGFs), macrophagecolony stimulating factor (M-CSF), granulocyte macrophage colonystimulating factor (GM-CSF), megakaryocyte derived growth factor (MGDF),keratinocyte growth factor (KGF), thrombopoietin, platelet-derivedgrowth factor (PGDF), novel erythropoiesis stimulating protein (NESP),bone morphogenetic protein (BMP), superoxide dismutase (SOD), tissueplasminogen activator (TPA), urokinase, streptokinase and kallikrein,and various human antibodies and humanized antibodies. The termproteins, as used herein, includes peptides, polypeptides, consensusmolecules, analogs, derivatives or combinations thereof.

In one embodiment of the present invention, the lyophilized formulationcomprises a model protein drug substance, recombinant human parathyroidhormone (PTH), with standard excipients, mannitol and phosphate.

Diluent to be used with the powders contained within the containerclosure assembly can also be customized for the best stability andpatient compliance. Diluents contemplated for use include commerciallyavailable water for injection (WFI), bacteriostatic water for injection(BWFI), or phosphate buffered saline (PBS), etc. Custom developeddiluent can further contain a buffering agent, e.g., acetate, phosphate,histidine, citrate, acetate, succinate, glutamate, and glycine;surfactants; stabilizers; tonicity modifiers like sodium chloride; metalions; local anesthetic agents like lidocaine or benzyl alcohol, andhydrogels for controlled release, etc.

Materials contemplated for use in the manufacturing of the productcontainer, top cup component, plug component and/or plunger assembly ofthe present invention include, e.g., cyclo olefin copolymer,polycarbonate, polystyrene, Teflon, and the like. Such materials arewell known to those of ordinary skill in the art and readily available.

The product container may vary in size and configuration but istypically cylindrical in shape, and has at one end an opening and at theother end an ejection port. An important, unique design feature of theproduct container is a spiral mixing channel that is integrated into theproduct container at the lower base. The spiral mixing channel serves toenhance the recovery of the powder due to fluid path within thecontainer. The product container will be specifically designed to hold asufficient volume of liquid active ingredient and specifically designedto accept a plunger assembly. At the ejection port end, the productcontainer may be specifically designed to: 1) allow attachment viafriction fit to either a luer-lock or luer-slip standard needle; 2)comprise a staked needle (with a needle shield); 3) comprise a nozzlespray tip for nasal delivery; or 4) comprise a blunt tip for oral orocular applications. In each configuration, the ejection port end of theproduct container will have a detachable base which serves to hold andstabilize the product container during filling and during thelyophilization process. In addition, the detachable base serves as aneedle shield when the ejection port end of the product containercomprises a staked needle.

The top cup component may vary in size and configuration and is capableof engaging with the plug component with a snug fit to form a plungerassembly having varying manufacturing and/or end user functionality. Thetop cup component may comprise a detachable tab seal which, when torquedand detached, allows for attachment via friction fit of the top cup toeither a luer-lock or luer-slip syringe. Alternatively, the top cup maycomprise a lock-ring cap in place of the tab seal. The top cup componentmay be specifically designed to comprise one or more fluid transferchannels which allows for diluent from the attached syringe to flowthrough the plunger assembly and encounter the lyophilized powder in theproduct container.

The plug component may vary in size and configuration and is capable ofengaging with the top cup component with a snug fit to form a plungerassembly having varying manufacturing and/or end user functionality. Theplug component will be specifically designed such that when fullyengaged with the top cup component to form a plunger assembly, there isminimal fluid head space, i.e., minimal holdup volume of the transferdiluent, and such that when the plunger assembly is fully engaged withthe product container the plunger assembly compresses the powderedactive ingredient and there is minimal fluid head space. The plugcomponent may be specifically designed to comprise one or more fluidtransfer channels which allows for diluent from the attached syringe toflow through the plunger assembly and encounter the lyophilized powderin the product container.

Also contemplated for use in the container closure assembly of thepresent invention is a one piece plunger assembly specifically designedto be accepted by the product container such that when the plungerassembly is fully engaged with the product container the plungerassembly compresses the powdered active ingredient and there is minimalfluid head space. The one piece plunger assembly will comprise: adetachable tab seal and luer lock tab fitting cavity to allow forfriction fit of a standard type luer slip syringe at the top end; acircular cavity that can accommodate a typical luer lock syringe; and adefined fluid transfer channel which facilitates flow of fluid throughsaid plunger assembly.

It is understood that the container closure assembly of the presentinvention may vary in size and is readily adaptable to and functionalwith any standard type pre-filled syringe and standard type needles.Such syringes and needles are well known to those of ordinary skill inthe art and readily available. Generally, the container physicaldimensions should be roughly no more than 25 mm×25 mm×150 mm and thecontainer should have provisions for filling up to 20 ml of liquidpharmaceutical product to be lyophilized.

In the improved process for the preparation of a container closureassembly containing a lyophilized powder product, 1) the empty productcontainer (with detachable base) is loaded into a industry standardvial/syringe/cartridge manufacturing filling line in a similar manner asregular vials, syringes, or cartridges; 2) the product container isfilled with an optimized liquid formulation containing a pharmaceuticalproduct; 3) a plunger assembly is dropped into an “open” position on topof the product container, engaging the product container in the samemanner as lyophilization stoppers are mounted to regular vials, creatinga container closure assembly; 4) the container closure assembly is thenplaced into the lyophilizer and subjected to a lyophilization process;5) during lyophilization, vapor escapes via the openings between theplunger assembly and the product container; 6) upon completion oflyophilization, vertical compression of the lyophilizer shelves willpush the plunger assembly into the product container creating a sealedcontainer closure assembly and compressing the dry powder to minimalhead space; and 7) the sealed container closure assembly is bonded toprovide a tamper resistant assembly which retains the sterility of theactive ingredient. Importantly, in this process, the plunger assembly ispushed down such that it compresses the pharmaceutical powder and thereis minimal air space between the product container and the plungerassembly. This design concept reduces the volume of air, reducesresidual drug at the completion of injection, and facilitates the directinjection of the lyophilized powder without the need for a separatereconstitution/mixing/priming step of powder with diluent.

Methods and techniques to be used to bond the sealed assembly are wellknown to those of ordinary skill in the art and include, e.g., gluing,welding. The bonding serves to help maintain seal integrity and providea tamper resistant assembly which retains the sterility of the activeingredient. As such, the bonded sealed container closure assembly of thepresent invention is able to retain the sterility of the pharmaceuticalpowder product and is storage stable at room temperature over the shelflife of the product.

In the improved method for the administration of a lyophilizedpharmaceutical product using the container closure assembly of thepresent invention, 1) the detachable tab seal on the top of the assemblyis removed by applying a tangential force thus exposing the top of theplunger assembly for attachment of a pre-filled syringe containing thediluent; 2) the detachable base located on the opposing ejection portend of the container closure assembly is removed, thus exposing aluer-slip tip for the attachment of a needle; 3) a luer-slip needle isattached via friction fit to the exposed luer-slip tip of the containerclosure assembly; 4) the injection is then initiated by inserting theneedle into the injection site; 5) force is applied to the syringeplunger whereupon the diluent in the syringe will be forced through theplunger assembly; 6) the diluent will be guided through a designed pathto encounter the lyophilized powder in the product container and rapidlyreconstitute; and 7) the reconstituted liquefied product mixture exitsthe container closure assembly through the ejection port, passes throughthe attached needle and into the injection site. As an alternative tosteps 2) and 3), the container closure assembly may have a staked needleat the ejection port end, which is exposed when the detachable base isremoved. In another embodiment, as an alternative to steps 2) and 3),the container closure assembly may comprise a nozzle spray tip at theejection port end which is exposed when the detachable base is removed.In yet another embodiment, as an alternative to steps 2) and 3), thecontainer closure assembly may comprise a blunt tip at the ejection portend which is exposed when the detachable base is removed. Importantly,none of the methods described above require a separatereconstitution/mixing/priming step, thereby providing for a moreconvenient and ease of use for the patient and/or end user.

Importantly, the improved delivery method of the present inventionprovides a ‘gradient delivery’ of the injectable pharmaceutical product.For example, because the present invention provides for the immediatereconstitution of the powdered drug upon contact with the diluent, theproduct is injected into the patient in a manner wherein more highlyconcentrated product is injected initially. It is the improved processand container closure assembly design concept described herein thatfacilitates the direct administration of the powdered active ingredient,without the need for a separate reconstitution/mixing step. It is thusenvisioned that the lyophilized formulations, lyophilization processesand closure assembly design concepts described herein could be appliedto existing delivery devices, e.g., pen systems, autoinjector systems,needle-free injector systems, dual-chambered injection cartridges and/orpre-filled syringe systems, to provide for improved methods ofadministration of powdered drugs which provide for gradient delivery andwhich are more user friendly for the patient and/or end user.

EXAMPLE 1

In this Example, a study was conducted to demonstrate the ‘gradientdelivery’ injection profile associated with the administration of apowdered drug using the formulations, lyophilization processes andcontainer closure assembly design of the present invention.

The study was performed utilizing a model protein drug substance,Recombinant Human Parathyroid Hormone (PTH) with standard excipients,mannitol and phosphate. The study was performed by using a sealedcontainer closure assembly prepared using the process of the presentinvention and containing 10 mg of PTH powder which was dried in atypical lyophilization process. A syringe containing 1 ml of diluent(water) was attached to the plunger assembly of the container closureassembly and the detachable base at the neck end of the containerclosure assembly was removed. Force is applied to the syringe plungersuch that the water flows through the assembly, reconstitutes thepowder, and the resultant solution drips out of the ejection port of theassembly. The concentration of PTH in each drop of solution was measuredwith a ultraviolet spectrometer. The data collected and shown in FIG. 10characterize the general profile of the gradient delivery associatedwith the administration of a powdered drug using the formulations,lyophilization processes and container closure assembly design of thepresent invention. As depicted in FIG. 10, the concentration of the dosedelivered over the injection volume for a gradient delivery is nonconstant with the bulk of the active pharmaceutical ingredient beingdelivered during the initial portion of the injection.

This unique gradient delivery of the injectable pharmaceutical powderproduct may be advantageous to the patient in certain therapeuticsettings. To date, none of the known prior art delivery techniques anddevices used for delivery of powdered drugs have such a profile, as allrequire a reconstitution and/or mixing step of the powdered drug with adiluent prior to injection, and therefore have an injection profilesimilar to that depicted in FIG. 11. Although this specific protein wasused, it is highly probable that for those skilled in the art and formost standard active pharmaceutical products, excipients and otheringredients that the same results can be achieved and will reflect thesesame characteristics and injection response.

The improved lyophilized formulations, lyophilization processes andclosure assembly design concepts of the present invention providepatients and end-users with an alternative, less expensive and easier touse device than current state-of-the-art delivery systems forlyophilized products. Utilization of the design concept described forcontainer closure assembly of the present invention on existing deliverydevices would provide a valuable and much needed benefit to thosepatients dependent upon powdered drugs in their therapeutic settings.

1. A container closure assembly suitable for lyophilized pharmaceuticalproducts comprising: a plunger assembly comprising: a luer lock tabfitting cavity to allow for friction fit of a standard type luer slipsyringe; a circular cavity that can accommodate a typical luer locksyringe; and a defined fluid transfer channel extending axially from theproximal end to the distal end of a plug component which facilitatesflow of fluid through said assembled plunger assembly; wherein saidfluid transfer channel is on the outside of the plug compartment and aproduct container component comprising: an open end having a chambercapable of holding a liquid active ingredient to be lyophilized anddesigned to accept said plunger assembly; a locking ridge integratedinto the sidewall of said product container; an opposing lower basecomprising a coaxial hollow ejection port; and a spiral mixing channelintegrated into said lower base.
 2. A container closure assemblysuitable for lyophilized pharmaceutical products comprising: a plugcomponent comprising: a defined fluid transfer channel extending axiallyfrom the proximal end to the distal end on the outside of the plugcomponent which allows for flow of fluid through said plug component; atop cup component comprising: a luer lock tab fitting cavity to allowfor friction fit of a standard type luer slip syringe; a circular cavitythat can accommodate a typical luer lock syringe; a hollow circularinside capable of accepting said plug component to create a plungerassembly; and a product container component comprising: an open endhaving a chamber capable of holding a liquid active ingredient to belyophilized and designed to accept said plunger assembly; a lockingridge integrated into the sidewall of said product container; anopposing lower base comprising a coaxial hollow ejection port; and aspiral mixing channel integrated into said lower base.